Cellular gatekeepers 'read' gene machinery

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That's what happened recently in Dr. Richard Young's laboratory at the Whitehead Institute for Biomedical Research. Dr. Young and Dr. Anthony Koleske were searching for new components of the complex machinery that switches genes on and off in living cells.

What they found will revolutionize the study of gene function and stimulate new directions in research on cancer, infectious disease and developmental biology.

Every cell in the human body faces a pivotal challenge: how to use the 100,000 genes encompassed in the genetic blueprint-the DNA-to carry out its specialized tasks. A brain cell has the same basic set of instructions as a kidney cell, yet they have very different structures and responsibilities-each cell must have a way of picking out the small subset of genes that will allow it to perform properly.

"The challenge is really two fold," explained Dr. Young, a member of the Whitehead Institute and a professor of biology at MIT. "The cell must select the correct genes and then decide how to use them. Each gene encodes the instructions for a single protein molecule. In many cases, the amount of protein product must be regulated very precisely. Thus, the cell cannot simply turn on a gene and begin producing protein molecules-it must also determine the rate of gene function, or the number of protein molecules produced over a given time period."

The discovery by Drs. Young and Koleske concerns this vital regulatory function. They have identified a set of molecules that appear to act as gatekeepers for the gene reading, or transcription, machinery.

"We weren't particularly surprised by the existence of these gatekeepers because we knew that the regulatory process would be extremely complex," Dr. Young said. "The real shocker came when we learned that the gatekeepers had a second function-they glue together other pieces of machinery in the cell to make a sort of super-factory for reading genes."

The Whitehead scientists described the super-factory, known as a holoenzyme, in the March 31 issue of Nature. The new gatekeeper proteins, called SRBs, represent the order department of this super-factory. They interact with other signals in the cell to determine which genes will be read and how often. "It's as if you had a factory capable of making many different products," Dr. Young says. "The SRBs process and direct customer orders to make sure that the product line is balanced and that supply equals demand."

Dr. Koleske, who recently completed his MIT doctoral thesis in the Young laboratory and is now a postdoctoral fellow at the Whitehead Institute, said that the discovery of the new holoenzyme has implications for many different fields of research. "Transcription is a fundamental part of every activity in the cell," he explained. "The new holoenzyme will become a natural focal point for understanding genetic control in development and disease."

For example, the Whitehead scientists suspect that the maturation of a cell may be accompanied by subtle changes in the make-up or composition of the SRBs. Similarly, the evolution of a healthy cell into a cancer cell may result in specific changes in the holoenzyme-understanding these changes could reveal important new targets for anti-cancer drugs. With respect to infectious disease, certain viral control elements already have been shown to influence the holoenzyme's activity.

"With the discovery of this holoenzyme, we have a new foundation for approaching many difficult questions in biology," Dr. Young said. "The SRBs were a crucial piece of the puzzle-we now have a much clearer picture of gene transcription inside living cells."

This work was funded by a grant from the National Institute of General Medical Sciences, National Institutes of Health.